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The SR/ER-mitochondria calcium crosstalk is regulated by GSK3? during reperfusion injury.

ABSTRACT: Glycogen synthase kinase-3? (GSK3?) is a multifunctional kinase whose inhibition is known to limit myocardial ischemia-reperfusion injury. However, the mechanism mediating this beneficial effect still remains unclear. Mitochondria and sarco/endoplasmic reticulum (SR/ER) are key players in cell death signaling. Their involvement in myocardial ischemia-reperfusion injury has gained recognition recently, but the underlying mechanisms are not yet well understood. We questioned here whether GSK3? might have a role in the Ca(2+) transfer from SR/ER to mitochondria at reperfusion. We showed that a fraction of GSK3? protein is localized to the SR/ER and mitochondria-associated ER membranes (MAMs) in the heart, and that GSK3? specifically interacted with the inositol 1,4,5-trisphosphate receptors (IP3Rs) Ca(2+) channeling complex in MAMs. We demonstrated that both pharmacological and genetic inhibition of GSK3? decreased protein interaction of IP3R with the Ca(2+) channeling complex, impaired SR/ER Ca(2+) release and reduced the histamine-stimulated Ca(2+) exchange between SR/ER and mitochondria in cardiomyocytes. During hypoxia reoxygenation, cell death is associated with an increase of GSK3? activity and IP3R phosphorylation, which leads to enhanced transfer of Ca(2+) from SR/ER to mitochondria. Inhibition of GSK3? at reperfusion reduced both IP3R phosphorylation and SR/ER Ca(2+) release, which consequently diminished both cytosolic and mitochondrial Ca(2+) concentrations, as well as sensitivity to apoptosis. We conclude that inhibition of GSK3? at reperfusion diminishes Ca(2+) leak from IP3R at MAMs in the heart, which limits both cytosolic and mitochondrial Ca(2+) overload and subsequent cell death.

SUBMITTER: Gomez L

PROVIDER: S-EPMC4716295 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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The SR/ER-mitochondria calcium crosstalk is regulated by GSK3β during reperfusion injury.

Gomez L L Thiebaut P-A PA Paillard M M Ducreux S S Abrial M M Crola Da Silva C C Durand A A Alam M R MR Van Coppenolle F F Sheu S-S SS Ovize M M

Cell death and differentiation 20150724 2

Glycogen synthase kinase-3β (GSK3β) is a multifunctional kinase whose inhibition is known to limit myocardial ischemia-reperfusion injury. However, the mechanism mediating this beneficial effect still remains unclear. Mitochondria and sarco/endoplasmic reticulum (SR/ER) are key players in cell death signaling. Their involvement in myocardial ischemia-reperfusion injury has gained recognition recently, but the underlying mechanisms are not yet well understood. We questioned here whether GSK3β mig ...[more]

PMID: 26206086

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Dataset Information

The SR/ER-mitochondria calcium crosstalk is regulated by GSK3? during reperfusion injury.

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The SR/ER-mitochondria calcium crosstalk is regulated by GSK3β during reperfusion injury.

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